Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex. Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).

Sandhoff disease comprises a phenotypic continuum encompassing acute infantile, subacute juvenile, and late-onset disease. Although classification into these phenotypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span. Acute infantile Sandhoff disease (onset age <6 months). Infants are generally normal at birth followed by progressive weakness and slowing of developmental progress, then developmental regression and severe neurologic impairment. Seizures are common. Death usually occurs between ages two and three years. Subacute juvenile Sandhoff disease (onset age 2-5 years). After attaining normal developmental milestones, developmental progress slows, followed by developmental regression and neurologic impairment (abnormal gait, dysarthria, and cognitive decline). Death (usually from aspiration) typically occurs in the early to late teens. Late-onset Sandhoff disease (onset older teen years or young adulthood). Nearly normal psychomotor development is followed by a range of neurologic findings (e.g., weakness, spasticity, dysarthria, and deficits in cerebellar function) and psychiatric findings (e.g., deficits in executive function and memory). Life expectancy is not necessarily decreased.

PLP1 disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.

Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (summary by Baresova et al., 2012).

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.

Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals.

Congenital glutamine deficiency (GLND) is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (summary by Haberle et al., 2011).

POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.

A very rare, complex form of hereditary spastic paraplegia characterised by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement (i.e. loss of finger dexterity, dysmetria), and mild cognitive impairment, without the presence of nystagmus. A hypomyelinating leucodystrophy and thin corpus callosum is observed in all cases and psychomotor development is normal or near normal. Caused by mutations in the GJC2 gene (1q41-q42) encoding the gap junction gamma-2 protein.

Developmental and epileptic encephalopathy-5 (DEE5) is a neurologic disorder characterized by global developmental delay and the onset of tonic seizures or infantile spasms in the first months of life. The seizures tend to be refractory to treatment, and EEG shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals have severely impaired psychomotor development with lack of visual attention, poor head control, feeding difficulties, microcephaly, and spastic quadriplegia. Brain imaging may show cerebral atrophy and hypomyelination (summary by Saitsu et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

The chromosome 8q21.11 deletion syndrome is characterized by impaired intellectual development and common facial dysmorphic features (summary by Palomares et al., 2011).

The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations (a few to hundreds of oval/circular macules or patches varying in size from 1-2 mm to several cm), hypoplastic distal phalanges of the hands and/or feet, early-onset intractable epilepsy, and profound developmental delay. Seizures, which can be focal, tonic, and complex partial and can include infantile spasms, appear to stabilize after age two years. Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be seen. To date, the diagnosis has been confirmed in 18 individuals from 15 families.

POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.

Neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures (NEDHCS) is an autosomal recessive syndrome characterized primarily by hypotonia and poor feeding apparent in early infancy. Affected individuals have severe global developmental delay, early-onset intractable seizures, and recognizable craniofacial dysmorphism with skull abnormalities. The disorder is believed to be unique to the Amish population, where it exhibits a founder effect (summary by Ammous et al., 2021).

Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 13 (CG13, equivalent to CGH) have mutations in the PEX13 gene. For information on the history of PBD complementation groups, see 214100.

Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by Zhang et al., 2014).

Severe combined immunodeficiency (SCID) due to DNA-PKcs deficiency is an extremely rare type of SCID (see this term) characterized by the classical signs of SCID (severe and recurrent infections, diarrhea, failure to thrive), absence of T and B lymphocytes, and cell sensitivity to ionizing radiation.

PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset problems can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common.

Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients present in infancy with delayed neurodevelopment, refractory seizures, hypotonia, and hearing impairment due to auditory neuropathy. Less common features may include cortical blindness, renal dysfunction, and/or liver involvement, suggestive of Alpers syndrome (MTDPS4A; 203700). Patients with the severe phenotype tend to have brain abnormalities on imaging, including cerebral atrophy and hyperintensities in the basal ganglia and brainstem, consistent with Leigh syndrome. Laboratory values may be normal or show increased lactate and evidence of mitochondrial respiratory chain defects, particularly in muscle. Some patients achieve little developmental milestones and may die in infancy or early childhood. However, some patients have a less severe phenotype manifest only by myopathy (summary by Sofou et al., 2015, Vanlander et al., 2015, and Mizuguchi et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) is an autosomal recessive disorder characterized by severe neurologic impairment including impaired intellectual development, epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (Tanaka et al., 2015).

POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.

Hypomyelinating leukodystrophy-10 (HLD10) is an autosomal recessive neurologic disorder characterized by postnatal progressive microcephaly, severely delayed psychomotor development, and hypomyelination on brain imaging (summary by Nakayama et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Developmental and epileptic encephalopathy-29 (DEE29) is an autosomal recessive neurologic disorder characterized by the onset of refractory myoclonic seizures in the first months of life. Affected individuals have poor overall growth, congenital microcephaly with cerebral atrophy and impaired myelination on brain imaging, spasticity with abnormal movements, peripheral neuropathy, and poor visual fixation (summary by Simons et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

NKX6-2-related disorder is characterized by a spectrum of progressive neurologic manifestations resulting from diffuse central nervous system hypomyelination. At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of early motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination) and cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia) with loss of developmental milestones. To date NKX6-2-related disorder has been reported in 25 individuals from 13 families.

Autosomal recessive limb-girdle muscular dystrophy-18 (LGMDR18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Hypomyelinating leukodystrophy-15 (HLD15) is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by Mendes et al., 2018) For a discussion of genetic heterogeneity of HLD, see 312080.

Developmental and epileptic encephalopathy (DEE93) is an autosomal dominant neurologic disorder characterized by delayed psychomotor development, early-onset refractory seizures, and impaired intellectual development. The severity of the phenotype is highly variable: some patients may be nonverbal and nonambulatory with spastic quadriparesis and poor eye contact, whereas others have moderate intellectual disability (summary by Fassio et al., 2018). For a discussion of genetic heterogeneity of DEE, see 308350.

A rare subtype of orofaciodigital syndrome, with autosomal recessive inheritance and C2CD3 mutations. The disease has characteristics of severe microcephaly, trigonocephaly, severe intellectual disability and micropenis, in addition to oral, facial and digital malformations (gingival frenulum, lingual hamartomas, cleft/lobulated tongue, cleft palate, telecanthus, up-slanting palpebral fissures, microretrognathia, postaxial polydactyly of hands and duplication of hallux). Corpus callosum agenesis and vermis hypoplasia with molar tooth sign on brain imaging are also associated.

Congenital hypomyelinating neuropathy-3 is an autosomal recessive neurologic disorder characterized by onset of neurogenic muscle impairment in utero. Affected individuals present at birth with severe hypotonia, often causing respiratory insufficiency or failure and inability to swallow or feed properly. They have profoundly impaired psychomotor development and may die in infancy or early childhood. Those that survive are unable to sit or walk. Sural nerve biopsy shows hypomyelination of the nerve fibers, and brain imaging often shows impaired myelination and cerebral and cerebellar atrophy. Nerve conduction velocities are severely decreased (about 10 m/s) or absent due to improper myelination (summary by Vallat et al., 2016 and Low et al., 2018). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

Huppke-Brendel syndrome (HBS) is characterized by bilateral congenital cataracts, sensorineural hearing loss, and severe developmental delay. To date, six individuals with HBS have been reported in the literature. All presented in infancy with axial hypotonia; motor delay was apparent in the first few months of life with lack of head control and paucity of limb movement. Seizures have been reported infrequently. In all individuals described to date serum copper and ceruloplasmin levels were very low or undetectable. Brain MRI examination showed hypomyelination, cerebellar hypoplasia mainly affecting the vermis, and wide subarachnoid spaces. None of the individuals reported to date were able to sit or walk independently. All affected individuals died between age ten months and six years.

Hypomyelination with brainstem and spinal cord involvement and leg spasticity is an autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild mental retardation. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013).

Combined oxidative phosphorylation deficiency-21 (COXPD11) is a severe multisystemic autosomal recessive disorder characterized by neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, foot deformities, or seizures, and all reported patients have died in infancy. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (summary by Garcia-Diaz et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (NEDMEHM) is an autosomal recessive neurometabolic disorder characterized by these cardinal features. Patients also show an exaggerated startle reflex in early infancy (Rodan et al., 2018).

Developmental and epileptic encephalopathy-75 (DEE75) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by onset of severe refractory seizures in the first months of life. Patients often have global developmental delay before the onset of seizures, and thereafter achieve few milestones. EEG usually shows multifocal spikes and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. They have severely impaired intellectual development with inability to walk, absent speech, and hypotonia with axial hyperreflexia. Brain imaging shows progressive cerebral atrophy, frontal lobe atrophy, white matter abnormalities, and delayed myelination. Since the disorder is due to mitochondrial dysfunction, some patients may develop other organ involvement, including cardiomyopathy or liver and renal dysfunction. Death may occur in childhood (summary by Yin et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).

Developmental and epileptic encephalopathy-78 (DEE78) is a severe neurologic disorder characterized by onset of refractory seizures in the first days or months of life followed by severely impaired intellectual development. Additional features may include cortical visual impairment, hypotonia, and abnormal movements, such as spasticity (summary by Butler et al., 2018). One family with an attenuated disease course has been reported (Maljevic et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Developmental and epileptic encephalopathy-79 (DEE79) is a severe neurologic disorder characterized by onset of refractory seizures in the first months of life. Affected individuals have severely impaired psychomotor development and may show hypotonia or spasticity. Brain imaging may show hypomyelination, cerebral atrophy, and thinning of the corpus callosum (summary by Butler et al., 2018 and Hernandez et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA) is an autosomal recessive disorder characterized by severe global developmental delay, usually with hypotonia and absence of spontaneous movements other than head control, impaired intellectual development with absent speech, distal contractures, progressive microcephaly, dysmorphic features, and distal skeletal abnormalities, such as rocker-bottom feet and clenched hands with camptodactyly. Brain imaging tends to show a simplified gyral pattern of the cerebral cortex, delayed myelination, thin corpus callosum, and hypoplasia of the brainstem and cerebellum. The disorder may be complicated by feeding and/or breathing difficulties, often resulting in death in infancy (summary by Magini et al., 2019).

Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (Ferdinandusse et al., 2017).

Developmental and epileptic encephalopathy-86 (DEE86) is an X-linked neurologic syndrome characterized by severe and persistent seizures associated with EEG abnormalities beginning in the first few months of life, global developmental delay, severe motor deficits, dystonic movements, and dysmorphic facial features (Lentini et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, severe to profound intellectual impairment, early-onset refractory seizures, hypotonia, failure to thrive, and progressive microcephaly. Brain imaging shows cerebral atrophy, thin corpus callosum, and myelination defects. Death in childhood may occur (summary by Marafi et al., 2020).

Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development with variable motor abnormalities, such as axial hypotonia, peripheral spasticity, dystonia, and poor coordination, resulting in the inability to sit or walk. Affected individuals have impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Dysmorphic features are generally not present. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood (summary by AlMuhaizea et al., 2020 and Diaz et al., 2020).

SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (Bedoni et al., 2020).

Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC) is an autosomal recessive disorder characterized by global developmental delay with variably impaired intellectual development. More severely affected individuals are nonverbal and do not achieve independent ambulation, whereas others develop some speech and can walk, or show regression later in childhood. Common features include axial hypotonia, peripheral spasticity, dystonia, cataracts, and seizures. Brain imaging usually shows cerebellar hypoplasia with variable additional abnormalities, such as thin corpus callosum, cerebral atrophy, and hypomyelination (summary by Meng et al., 2021).

Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia (NEDFACH) is an autosomal recessive disorder characterized by global developmental delay and intellectual disability. The phenotype is variable: more severely affected individuals have poor overall growth with microcephaly, delayed walking, spasticity, and poor or absent speech, whereas others may achieve more significant developmental milestones and even attend special schooling. Brain imaging shows abnormalities of the cerebellum, most commonly cerebellar hypoplasia, although other features, such as thin corpus callosum and delayed myelination, may also be present. Dysmorphic facial features include sloping forehead, upslanting palpebral fissures, and hypertelorism. Additional more variable manifestations may include cardiac ventricular septal defect, spasticity, cataracts, optic nerve hypoplasia, seizures, and joint contractures (summary by Van Bergen et al., 2020).

Marbach-Rustad progeroid syndrome (MARUPS) is characterized by progeroid appearance with little subcutaneous fat and triangular facies, growth retardation with short stature, hypoplastic mandible crowded with unerupted supernumerary teeth, and cerebellar intention tremor. Psychomotor development is normal. Although features are reminiscent of Hutchinson-Gilford progeria syndrome (HGPS; 176670), MARUPS is less severe, with a relatively good prognosis. Two patients have been reported (Marbach et al., 2019).

Hypomyelinating leukodystrophy-22 (HLD22) is a neurologic disorder characterized by global developmental delay with mildly impaired intellectual development and marked motor impairment with limited or no ability to walk and dysarthria. Affected individuals have limb spasticity with pyramidal signs, as well as nystagmus, hypermetropia, and astigmatism. Brain imaging shows hypomyelination and a delay in myelination, although serial imaging shows some progress in both the central and peripheral white matter regions (Riedhammer et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Combined oxidative phosphorylation deficiency-53 (COXPD53) is an autosomal recessive disorder characterized by hypomyelination, microcephaly, liver dysfunction, and recurrent autoinflammation (summary by Lausberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).

Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC) is an autosomal recessive primarily neurologic disorder with variable manifestations. Common features included infantile-onset hypotonia, poor motor development, poor feeding and overall growth, and ataxic gait due to cerebellar ataxia. Other features include dysarthria, nystagmus, variable ocular anomalies, spasticity, hyperreflexia, and nonspecific dysmorphic features. Most, but not all, patients have global developmental delay with impaired intellectual development and speech delay. Brain imaging shows cerebellar hypoplasia, often with brainstem hypoplasia, enlarged ventricles, delayed myelination, and thin corpus callosum. A significant number of patients develop cardiac conduction defects in childhood or adolescence, often requiring pacemaker placement (summary by Slavotinek et al., 2020).

Neurodevelopmental disorder with impaired language and ataxia and with or without seizures (NEDLAS) is characterized by axial hypotonia and global developmental delay apparent in early infancy. Affected individuals have delayed walking with gait ataxia and poor language development. Behavioral abnormalities also commonly occur. The severity is highly variable: a subset of patients have a more severe phenotype with early-onset seizures resembling epileptic encephalopathy, inability to walk or speak, and hypomyelination on brain imaging (summary by Stolz et al., 2021).

Hypomyelinating leukodystrophy-23 with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy (HLD23) is an autosomal recessive neurodegenerative disorder with systemic manifestations. Affected individuals show delayed motor development and ataxic gait in early childhood that progresses to spastic paraplegia with loss of ambulation in the first decades of life. Additional features include progressive sensorineural hearing loss resulting in deafness, hepatic dysfunction with elevated liver enzymes, and dilated cardiomyopathy that ultimately results in death in the first or second decades. Brain imaging shows hypomyelination, diffuse white matter abnormalities consistent with leukodystrophy, and thin corpus callosum (summary by Sferra et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016).

PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.

Neurodevelopmental disorder with language delay and seizures (NEDLDS) is an autosomal recessive disorder characterized by global developmental delay with mild to severely impaired intellectual development and speech delay with poor or absent language. Affected individuals develop early-onset seizures that are usually well-controlled with medication. Additional features may include axial hypotonia, peripheral hypertonia, hypothyroidism, and nonspecific dysmorphic features or brain imaging abnormalities (Lu et al., 2022).

Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures (NEDMIMS) is an autosomal recessive disorder characterized by severe global developmental delay apparent from infancy, impaired intellectual development, progressive microcephaly, and early-onset seizures that may be refractory to treatment. Affected individuals have poor overall growth and may have various movement abnormalities, including hypo- and hypertonia. Behavioral problems may also be observed (Klockner et al., 2022).

Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2) is an autosomal recessive syndromic disorder characterized by onset of this constellation of features in infancy, resulting in death in early childhood. Telomeres are shortened, but classic mucocutaneous features of DKCB1 are not typically observed. CHINE2 is due to a ribosomal pseudouridylation defect (Balogh et al., 2020). See also CHINE1 (301108), caused by mutation in the DKC1 gene (300126).

Hypomyelinating leukodystrophy-27 (HLD27) is an autosomal recessive neurologic disorder characterized by global developmental delay with impaired motor and intellectual development apparent from infancy. Affected individuals have poor or absent speech, ataxic gait or inability to sit or walk, spasticity, and abnormal eye movements (nystagmus, gaze palsy). Some patients have seizures. Disease progression and developmental regression consistent with neurodegeneration is often observed. Brain imaging shows progressive hypomyelinating leukodystrophy, cerebral and cerebellar atrophy, and thin corpus callosum (Misceo et al., 2023). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Developmental and epileptic encephalopathy-116 (DEE116) is an autosomal dominant disorder characterized by severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry (Jones et al., 2024).